CN102153479A - Recovering and applying method of triethylamine in acylation liquid for preparing levofloxacin 1 - Google Patents
Recovering and applying method of triethylamine in acylation liquid for preparing levofloxacin 1 Download PDFInfo
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Abstract
The invention relates to a recovering and applying method of triethylamine in an acylation liquid for preparing levofloxacin 1 by a 2,3,4,5-tetrachloro benzoyl chloride acxylation method, belonging to the technical field of fine chemicals. The method is realized by the following steps: 1) filtering the acylation liquid in the process of preparing the levofloxacin by using the 2,3,4,5-tetrachloro benzoyl chloride acxylation method, so as to separate out the triethylamine, wherein the filtrate is an acylated mother liquid, and a filter cake is triethylamine hydrochloride; and 2) adding liquid alkaline to regulate the filter cake triethylamine hydrochloride to alkalinity, so that the triethylamine hydrochloride is converted into the triethylamine hydrochloride to be separated out, extracting with an organic solvent, dehydrating and converting for synthesis. The triethylamine recovering method is simple to operate, rectification is not needed, and the recovery rate is high and reaches above 93% which is equivalent to the fact that about 35 kg of triethylamine is just added in production of 1 ton of levofloxacin 1, and for expensive triethylamine, production cost is greatly reduced.
Description
Technical field
The invention belongs to the fine chemical technology field, be specifically related to a kind of 2,3,4, the recovery using method of triethylamine in the levofloxacin acidylate liquid that 5-four Benzoyl chloride acidylate methods are produced.
Background technology
Levofloxacin (Levofloxacin 1) chemistry is by name: (S)-(-)-and 9-fluoro-2,3-dihydro-3-methyl isophthalic acid 0-(4-methyl isophthalic acid-piperazinyl)-7-oxo-7H-pyridine benzene a pair of horses going side by side [1,2,3-de]-[1,4] benzene a pair of horses going side by side oxazines-6-carboxylic acid semihydrate, it is first tetrafluoro carbostyril family antibacterial drugs that gets the Green Light and produce of China, belong to national essential drugs, it has anti-microbial effect, its antibacterial strength is 2 times of Ofloxacine USP 23, toxicity is lower than Ofloxacine USP 23, is widely used in respiratory tract infection clinically, urinary tract infection, gynecological infection, the liver road infects, the treatment of ophthalmology infection and intestinal tract infections.The structure of levofloxacin is as follows:
Much produce house at present all with 2,3,4,5-four Benzoyl chlorides are raw material, by the levofloxacin of series reaction such as acidylate production.This technology need use a large amount of triethylamines to make catalyzer when acidylate; 1 ton of levofloxacin of every production approximately need drop into the triethylamine about 500 kilograms; and costing an arm and a leg of triethylamine; therefore it is carried out high efficiency recovery; not only can reduce the production cost of levofloxacin greatly, and also very significant to the discharging, the protection environment that reduce pollutent.Present 2,3,4, the levofloxacin acidylate liquor treating process that 5-four Benzoyl chloride acidylate methods are produced mainly is: with the unprocessed the next step that is directly used in of acidylate liquid, do not reclaim triethylamine then, directly triethylamine hydrochloride is removed in washing.Triethylamine is difficult for handling in this processing wastewater, and is seriously polluted, causes production cost higher simultaneously.
Summary of the invention
At the above-mentioned problems in the prior art, the object of the present invention is to provide a kind of 2,3,4, the recovery using method of triethylamine in the levofloxacin acidylate liquid that 5-four Benzoyl chloride acidylate methods are produced.
The recovery using method of triethylamine in described a kind of acidylate liquid for preparing levofloxacin, described acidylate liquid is with 2,3; 4; 5-four Benzoyl chlorides are raw material, and triethylamine is that catalyzer carries out the reaction solution that obtains after the acylation reaction, it is characterized in that described recovery using method comprises the steps:
1) will be with 2,3,4,5-four Benzoyl chlorides are for after the raw material acylation reaction finishes, and the acidylate liquid that obtains filters, and filtrate is carried out the next step for the acidylate mother liquor, and filter cake is a triethylamine hydrochloride;
2) filter cake that obtains in the step 1) is extremely alkaline with the liquid caustic soda adjust pH, make triethylamine hydrochloride change into triethylamine, obtain mixed solution;
3) with step 2) in the mixed solution that obtains be heated to 20-45 ℃, with organic solvent extraction 2-5 time, merge organic phase, adding must behind the desiccant dehydration;
4) solution that contains triethylamine that obtains in the step 3) is made into corresponding concentration, carries out doing the catalyzer use in the acylation reaction next time.
The recovery using method of triethylamine is characterized in that step 2 in described a kind of acidylate liquid for preparing levofloxacin) described in liquid caustic soda be the sodium hydroxide of concentration 10-50wt%.
The recovery using method of triethylamine is characterized in that step 2 in described a kind of acidylate liquid for preparing levofloxacin) described in the pH value transfer to 10-14.
The recovery using method of triethylamine is characterized in that the mixed solution described in the step 3) is heated to 25-30 ℃ in described a kind of acidylate liquid for preparing levofloxacin.
The recovery using method of triethylamine is characterized in that the organic solvent described in the step 3) is a toluene in described a kind of acidylate liquid for preparing levofloxacin, and its consumption is 2,3,4, and the 2-10 of 5-four Benzoyl chloride quality doubly.
The recovery using method of triethylamine is characterized in that the corresponding concentration described in the step 3) is the weight percent that triethylamine accounts for solvent toluene, is 9.1wt% in described a kind of acidylate liquid for preparing levofloxacin.
The recovery using method of triethylamine is characterized in that step 2 in described a kind of acidylate liquid for preparing levofloxacin) described in liquid caustic soda be the sodium hydroxide of concentration 20-40wt%.
The recovery using method of triethylamine is characterized in that step 2 in described a kind of acidylate liquid for preparing levofloxacin) described in the pH value transfer to 12.
The recovery using method of triethylamine is characterized in that the organic solvent described in the step 3) is a toluene in described a kind of acidylate liquid for preparing levofloxacin, and its consumption is 2,3,4, and the 3-6 of 5-four Benzoyl chloride quality doubly.
By above-mentioned technology, compared with prior art, beneficial effect of the present invention is as follows: this triethylamine recovery method, and simple to operate, need not rectifying, rate of recovery height reaches more than 93%, and 1 ton of levofloxacin of every production approximately need drop into the triethylamine about 500 kilograms, have among the present invention after 93% amount reclaims, be equivalent to 1 ton of levofloxacin of every production and only need drop into triethylamine about 35 kilograms, concerning expensive triethylamine, greatly reduce production cost.Therefore the present invention carries out high efficiency recovery to it, repeats to apply mechanically, and is effective, reduced production cost, increases economic efficiency, and is suitable for industrialization and produces product.
Embodiment
Below by embodiment, foregoing of the present invention is described in further detail, embodiment is to further explanation of the present invention, never is limitation of the present invention.Do not breaking away under the above-mentioned technological thought situation of the present invention, the various replacements of making according to ordinary skill knowledge and habitual means or the modification of change include within the scope of the invention.
Preparation levofloxacin acylation process embodiment:
Adopt 2,3,4; 5-four Benzoyl chloride acidylate legal systems are equipped with in the technology of levofloxacin, and with 43.8g N, N-dimethyl ethyl and 350g 9.1wt% triethylamine/toluene solution adds reaction flask; the oil bath temperature control drips 2,3 to 30-40 ℃; 4; (63.6g 0.3mol), dropwised 5-four Benzoyl chlorides in about 1 hour; drip and finish 60-65 ℃ of back temperature control, reacted 3 hours.Then reaction solution is cooled to room temperature, filters, filtrate is directly used in the next step, obtains filter cake triethylamine hydrochloride 41.3g.
Embodiment 1
With above-mentioned filter cake triethylamine hydrochloride, regulate PH to 12 with 10%NaOH, be heated to 25 ℃, divide three extractions with 210g toluene, extraction liquid dewaters through calcium oxide, obtains dry triethylamine/toluene solution 234g, triethylamine content 12.5wt%, the rate of recovery 96.5%, the method for calculation of the rate of recovery are the ratio of the amount of triethylamine in the amount of triethylamine in 234g triethylamine/toluene solution and the 41.3g filter cake triethylamine hydrochloride.
Embodiment 2
With above-mentioned filter cake triethylamine hydrochloride, regulate PH to 12 with 20%NaOH, be heated to 25 ℃, divide three extractions with 300g toluene, extraction liquid dewaters through calcium oxide, obtains dry triethylamine/toluene solution 326.1g, triethylamine content 9.23wt%, the rate of recovery 99.3%.
Embodiment 3
With above-mentioned filter cake triethylamine hydrochloride, regulate PH to 14 with 30%NaOH, be heated to 25 ℃, divide three extractions with 300g toluene, extraction liquid dewaters through calcium oxide, obtains dry triethylamine/toluene solution 328g, triethylamine content 9.15wt%, the rate of recovery 99%.
Embodiment 4
With above-mentioned filter cake triethylamine hydrochloride, regulate PH to 10 with 30%NaOH, be heated to 30 ℃, divide three extractions with 300g toluene, extraction liquid dewaters through calcium oxide, obtains dry triethylamine/toluene solution 325g, triethylamine content 8.67wt%, the rate of recovery 93%.
Embodiment 5
With above-mentioned filter cake triethylamine hydrochloride, regulate PH to 12 with 30%NaOH, be heated to 30 ℃, divide three extractions with 500g toluene, extraction liquid dewaters through calcium oxide, obtains dry triethylamine/toluene solution 527g, triethylamine content 5.74wt%, the rate of recovery 99.8%.
Embodiment 6
With above-mentioned filter cake triethylamine hydrochloride, regulate PH to 12 with 30%NaOH, be heated to 45 ℃, divide five extractions with 500g toluene, extraction liquid dewaters through calcium oxide, obtains dry triethylamine/toluene solution 526g, triethylamine content 5.53wt%, the rate of recovery 96%.
Embodiment 7
With above-mentioned filter cake triethylamine hydrochloride, regulate PH to 14 with 50%NaOH, be heated to 20 ℃, divide four extractions with 400g toluene, extraction liquid dewaters through calcium oxide, obtains dry triethylamine/toluene solution 428g, triethylamine content 6.98wt%, the rate of recovery 98.6%.
Embodiment 8
With above-mentioned filter cake triethylamine hydrochloride, regulate PH to 10 with 40%NaOH, be heated to 35 ℃, divide reextraction with 636g toluene, extraction liquid dewaters through calcium oxide, obtains dry triethylamine/toluene solution 661g, triethylamine content 4.36wt%, the rate of recovery 95.1%.
Reclaim triethylamine/toluene solution and prepare levofloxacin acylation process embodiment:
To obtain triethylamine/toluene solution (234g, triethylamine content 12.5wt%) in the example 1, add 113.4g toluene and 2.6g triethylamine, be made into 350g 9.1wt% triethylamine/toluene solution, be used for acylation reaction.
With 43.8g N, the 350g 9.1wt% triethylamine of N-dimethyl ethyl and above-mentioned preparation/toluene solution adds reaction flask, and the oil bath temperature control drips 2 to 30-40 ℃, 3,4, and 5-four Benzoyl chlorides (63.6g, 0.3mol), dropwised in about 1 hour, and dripped and finish 60-65 ℃ of back temperature control, reacted 3 hours.Then reaction solution is cooled to room temperature, filters, filtrate is directly used in the next step, obtains filter cake triethylamine hydrochloride 41.3g.Experimental result is consistent with new triethylamine.
Be used for above-mentioned reaction with arbitrary recovery liquid among the embodiment 2-8, all can obtain identical effect.
The above, only being preferred embodiments of the present invention, is not that the present invention is done any pro forma restriction, and every foundation technical spirit of the present invention is to any simple modification that above embodiment did, equivalent variations and modification all still belong in the scope of technical solution of the present invention.
Claims (9)
1. the recovery using method of triethylamine in the acidylate liquid for preparing levofloxacin, described acidylate liquid is with 2,3; 4; 5-four Benzoyl chlorides are raw material, and triethylamine is that catalyzer carries out the reaction solution that obtains after the acylation reaction, it is characterized in that described recovery using method comprises the steps:
1) will be with 2,3,4,5-four Benzoyl chlorides are for after the raw material acylation reaction finishes, and the acidylate liquid that obtains filters, and filtrate is carried out the next step for the acidylate mother liquor, and filter cake is a triethylamine hydrochloride;
2) filter cake that obtains in the step 1) is extremely alkaline with the liquid caustic soda adjust pH, make triethylamine hydrochloride change into triethylamine, obtain mixed solution;
3) with step 2) in the mixed solution that obtains be heated to 20-45 ℃, with organic solvent extraction 2-5 time, merge organic phase, adding must behind the desiccant dehydration;
4) solution that contains triethylamine that obtains in the step 3) is made into corresponding concentration, carries out doing the catalyzer use in the acylation reaction next time.
2. the recovery using method of triethylamine is characterized in that step 2 in a kind of acidylate liquid for preparing levofloxacin according to claim 1) described in liquid caustic soda be the sodium hydroxide of concentration 10-50wt%.
3. the recovery using method of triethylamine is characterized in that step 2 in a kind of acidylate liquid for preparing levofloxacin according to claim 1) described in the pH value transfer to 10-14.
4. the recovery using method of triethylamine is characterized in that the mixed solution described in the step 3) is heated to 25-30 ℃ in a kind of acidylate liquid for preparing levofloxacin according to claim 1.
5. the recovery using method of triethylamine is characterized in that the organic solvent described in the step 3) is a toluene in a kind of acidylate liquid for preparing levofloxacin according to claim 1, and its consumption is 2,3,4, and the 2-10 of 5-four Benzoyl chloride quality doubly.
6. the recovery using method of triethylamine is characterized in that the corresponding concentration described in the step 3) is the weight percent that triethylamine accounts for solvent toluene, is 9.1wt% in a kind of acidylate liquid for preparing levofloxacin according to claim 2.
7. the recovery using method of triethylamine is characterized in that step 2 in a kind of acidylate liquid for preparing levofloxacin according to claim 2) described in liquid caustic soda be the sodium hydroxide of concentration 20-40wt%.
8. the recovery using method of triethylamine is characterized in that step 2 in a kind of acidylate liquid for preparing levofloxacin according to claim 3) described in the pH value transfer to 12.
9. the recovery using method of triethylamine is characterized in that the organic solvent described in the step 3) is a toluene in a kind of acidylate liquid for preparing levofloxacin according to claim 5, and its consumption is 2,3,4, and the 3-6 of 5-four Benzoyl chloride quality doubly.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103115922A (en) * | 2013-03-04 | 2013-05-22 | 重庆紫光国际化工有限责任公司 | Method for determining content of triethylamine salt |
| CN103936671A (en) * | 2014-05-06 | 2014-07-23 | 启东东岳药业有限公司 | Preparation method for montelukast sodium intermediate |
| CN104292197A (en) * | 2014-09-19 | 2015-01-21 | 江苏安邦电化有限公司 | Synthesis method of spirodiclofen |
| CN109796413A (en) * | 2019-01-24 | 2019-05-24 | 安徽广信农化股份有限公司 | A kind of triethylamine recovery process for the synthesis of 4,6- dichloro pyrimidine |
| CN116062829A (en) * | 2022-12-12 | 2023-05-05 | 内蒙古鄂尔多斯电力冶金集团股份有限公司 | Non-temperature-changing extraction crystallization desalination method |
Citations (1)
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| CN101659669A (en) * | 2009-09-04 | 2010-03-03 | 浙江嘉善诚达药化有限公司 | Method for preparing levofloxacin |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101659669A (en) * | 2009-09-04 | 2010-03-03 | 浙江嘉善诚达药化有限公司 | Method for preparing levofloxacin |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103115922A (en) * | 2013-03-04 | 2013-05-22 | 重庆紫光国际化工有限责任公司 | Method for determining content of triethylamine salt |
| CN103115922B (en) * | 2013-03-04 | 2015-07-01 | 重庆紫光国际化工有限责任公司 | Method for determining content of triethylamine salt |
| CN103936671A (en) * | 2014-05-06 | 2014-07-23 | 启东东岳药业有限公司 | Preparation method for montelukast sodium intermediate |
| CN103936671B (en) * | 2014-05-06 | 2015-10-28 | 启东东岳药业有限公司 | The preparation method of montelukast sodium intermediate |
| CN104292197A (en) * | 2014-09-19 | 2015-01-21 | 江苏安邦电化有限公司 | Synthesis method of spirodiclofen |
| CN104292197B (en) * | 2014-09-19 | 2016-07-06 | 江苏安邦电化有限公司 | A kind of synthetic method of Envidor |
| CN109796413A (en) * | 2019-01-24 | 2019-05-24 | 安徽广信农化股份有限公司 | A kind of triethylamine recovery process for the synthesis of 4,6- dichloro pyrimidine |
| CN116062829A (en) * | 2022-12-12 | 2023-05-05 | 内蒙古鄂尔多斯电力冶金集团股份有限公司 | Non-temperature-changing extraction crystallization desalination method |
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